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The findings from Tony Wyss-Coray’s group suggest that that downregulation of neuronal TGF-βRII not only seems to “sensitize” neurons to injury in the context of Alzheimer pathology, but it also seems to amplify Alzheimer pathology by promoting amyloidosis. In particular, the authors found elevated levels of neocortical and hippocampal Aβ1-42 in older AD mice crossed with mice expressing the dominant negative receptor, and in vitro, genetic or pharmacologic knockdown of TGF-β signaling resulted in both neuronal loss and enhanced release of Aβ.

How do these findings dovetail with our work presented at the SfN meeting? Tony’s group has directly blocked TGF-β signaling in neurons by inducibly overexpressing a dominant negative TGF-βRII construct (lacking the signaling domain—very similar to what I am using), and they then crossed these mice to PDAPP AD mice to directly address the question of whether depriving neurons of the neurotrophic TGF-β signal promotes neuronal injury in the context of AD pathology. In my system I’ve driven the dominant negative TGF-βRII by the CD11c promoter (expressed by most cells of the innate immune system, including macrophages and dendritic cells) and crossed these mice to the Tg2576 AD mice to address the question of whether inhibiting TGF-β signaling on innate immune cells alters AD-like pathology. As Tony points out, TGF-β is a pleiotropic cytokine, which can have differing effects depending on concentration and cell type receiving the signal. He shows that blocking this signal on neurons is deleterious in the AD paradigm because it deprives these cells of an important neurotrophic signal. In my system, blocking TGF-β signaling in innate immune cells “revs these cells up” and causes them to clear Aβ/β-amyloid both in vivo and in vitro. Specifically, it seems that it is the peripheral macrophages that are the effectors in this response, as blockade of TGF-β in these cells causes them to enter into the brain and likely clear Aβ/β-amyloid. This response is not accompanied by proinflammatory cytokine production in vivo or in vitro, so it seems that this form of macrophage “activation” is beneficial because it promotes Aβ/β-amyloid phagocytosis in the absence of an overt inflammatory response. I guess the key message is that if we are going to target TGF-β as a therapeutic modality for AD, we have to be careful about where in the body we modulate this pathway; we’d ideally like to promote this pathway in neurons and block it in peripheral macrophages.